Cardiac myocytes stimulated with so-called paired, coupled, bi-geminal or intercalated pacing stimulation produce enhanced mechanical function on subsequent depolarizations of the heart. Herein, this type of cardiac pacing therapy is referred to as extra-systolic stimulation (ESS) which refers to delivery of cardiac pacing therapy soon after either an intrinsic or pacing-induced systole. The magnitude of the enhanced mechanical function is strongly dependent on the timing of the extra systole relative to the preceding intrinsic or paced systole. When correctly timed, an ESS pulse causes depolarization of the heart but the attendant mechanical contraction is absent or substantially weakened. The contractility of the subsequent cardiac cycles, referred to as the post-extra-systolic beats, is increased as described in detail in commonly assigned U.S. Pat. No. 5,213,098 issued to Bennett et al., incorporated herein by reference in its entirety. The mechanism for stroke volume augmentation and other effects of ESS therapy is thought to be related to the calcium cycling within the myocytes. The extra systole initiates a limited calcium release from the sarcolasmic reticulum (SR). The limited amount of calcium that is released in response to the extra systole is not enough to cause a normal mechanical contraction of the heart. After the extra systole, the SR continues to take up calcium with the result that subsequent depolarization(s) cause a large release of calcium from the SR, resulting in vigorous myocyte contraction.
As noted, the degree of mechanical augmentation on post-extra-systolic beats depends strongly on the timing of the extra systole following a first depolarization, referred to as the “extrasystolic interval” (ESI). If the ESI is too long, the effects of ESS therapy are not achieved because a normal mechanical contraction takes place in response to the extra-systolic stimulus. As the ESI is shortened, a maximal effect is reached when the ESI is slightly longer than the physiological refractory period. An electrical depolarization occurs without a mechanical contraction or with a substantially weakened contraction. When the ESI becomes too short, the stimulus falls within the absolute refractory period and no depolarization occurs.
One method for quantifying the effect of extra-systolic stimulation includes measuring a parameter indicative of myocardial contractile function on a pre-extra-systolic beat or beats and on a post-extra-systolic beat or beats and determining the ratio of these measures, which may be referred to as the “potentiation ratio” or “PR.” The potentiation effect following an extra systole will generally persist for several post-extra-systolic beats before the contractile function returns to the baseline, pre-extra-systolic function. The rate of decay of the potentiation effect is referred to as the “recirculation fraction” or “RF.” A return to baseline contractile function after a period of extra-systolic stimulation typically occurs within about six heart beats. However, RF may be higher or lower depending on the calcium handling properties of the myocardium which may be affected by the disease state of heart failure.
The above-cited patent to Bennett et al. generally discloses a paired pacing cardiac stimulator for the treatment of congestive heart failure or other cardiac dysfunctions. A cardiac performance index is developed from a sensor employed to monitor the performance of the heart, and a cardiac stress index is developed from sensor employed to monitor the cardiac muscle stress. Either or both the cardiac performance index and cardiac stress index may be used in controlling the delivery of PESP stimulation. Prior non-provisional U.S. patent application Ser. No. 10/322,792 filed 28 Aug. 2002, in which was issued into U.S. Pat. No. 6,738,667 on May 18, 2004, and corresponding PCT application (publication no. WO 02/053026) by Deno et al., which is hereby incorporated herein by reference in its entirety, discloses an implantable medical device for delivering post extra-systolic potentiation stimulation. PESP stimulation is employed to strengthen the cardiac contraction when one or more parameters indicative of the state of heart failure show that the heart condition has progressed to benefit from increased contractility, decreased relaxation time, and increased cardiac output PCT Publication WO 01/58518 (still pending) by Darwish et al., incorporated herein by reference in its entirety, generally discloses an electrical cardiac stimulator for improving the performance of the heart by applying paired pulses to a plurality of ventricular sites. Multi-site paired pacing is proposed to increase stroke work without increasing oxygen consumption and, by synchronizing the timing of the electrical activity at a plurality of sites in the heart, decrease a likelihood of development of arrhythmia.
As indicated in the referenced '098 patent, a possible confounding factor to broad utilization of ESS stimulation is potential for arrhythmia induction. If the extra-systolic pulse is delivered to cardiac cells during the vulnerable period, the risk of inducing tachycardia or fibrillation in arrhythmia-prone patients can increase. Thus, it is clear that an extra-systolic pulse must be delivered safely after the vulnerable period but within a limited window of time for achieving effective stroke volume augmentation and other effects of ESS therapy.